Bendamustine is a nitrogen mustard used in the treatment of chronic lymphocytic leukemias and lymphomas and is also being studied for the treatment of sarcoma. It belongs to the family of drugs referred to as alkylating agents.
The synthesis of bendamustine hydrochloride monohydrate has been reported by Ozegowski and Krebs, J. Praktische Chemie, 4(20), 178-186 (1963) and by Gao et al., Chinese Journal of New Drugs, 16(23), 1960-1, 1970 (2007). The synthetic sequences described in these publications involve a step wherein ethyl 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate is converted to ethyl 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate by reaction of the former compound with two equivalents of ethylene oxide. However, this approach may lead to the generation of undesired side products such as those produced from further reaction of the terminal hydroxyl group(s) of the target compound with ethylene oxide. In other words, the ethyl 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate may further react with additional ethylene oxide to introduce oligooxyethylene groups into the molecule. Additionally, although it is currently used in many industrial applications, ethylene oxide is recognized as a very hazardous substance. At room temperature, it is a flammable, carcinogenic, mutagenic, irritating and anesthetic gas with a misleadingly pleasant aroma. Its use in the routine large scale production of bendamustine would therefore pose serious safety and handling issues.
Accordingly, it would be desirable to develop alternative approaches for synthesizing alkyl esters of 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butyric acid, such as ethyl 4-(5-(bis(2-hydroxyethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate, which avoid the use of ethylene oxide as a reactant and which have reduced potential for the generation of by-products.